Journal article
Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature.
- Casini A Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.
- Sokollik C Paediatric Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Inselspital, University of Bern, Bern, Switzerland.
- Lukowski SW Department of Genetic Medicine and Development, University Medical School of Geneva, Geneva, Switzerland.
- Lurz E Paediatric Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Inselspital, University of Bern, Bern, Switzerland.
- Rieubland C Division of Human Genetics, Department of Paediatrics, Inselspital, Bern, Switzerland.
- de Moerloose P Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.
- Neerman-Arbez M Angiology and Haemostasis, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland.
- 2015-05-21
Published in:
- Haemophilia : the official journal of the World Federation of Hemophilia. - 2015
congenital fibrinogen disorders
genetics
hypofibrinogenemia
liver disease
molecular models
mutation
Adolescent
Adult
Afibrinogenemia
Aged
Child
Child, Preschool
Female
Fibrinogen
Humans
Liver Diseases
Male
Middle Aged
Models, Molecular
Mutation
Pedigree
Protein Conformation
Young Adult
English
INTRODUCTION
Fibrinogen storage disease (FSD) is characterized by hypofibrinogenemia and hepatic inclusions due to impaired release of mutant fibrinogen which accumulates and aggregates in the hepatocellular endoplasmic reticulum. Liver disease is variable.
AIM
We studied a new Swiss family with fibrinogen Aguadilla. In order to understand the molecular peculiarity of FSD mutations, fibrinogen Aguadilla and the three other causative mutations, all located in the γD domain, were modelled.
METHOD
The proband is a Swiss girl aged 4 investigated because of fatigue and elevated liver enzymes. Protein structure models were prepared using the Swiss-PdbViewer and POV-Ray software.
RESULTS
The proband was found to be heterozygous for fibrinogen Aguadilla: FGG Arg375Trp. Familial screening revealed that her mother and maternal grandmother were also affected and, in addition, respectively heterozygous and homozygous for the hereditary haemochromatosis mutation HFE C282Y. Models of backbone and side-chain interactions for fibrinogen Aguadilla in a 10-angstrom region revealed the loss of five H-bonds and the gain of one H-bond between structurally important amino acids. The structure predicted for fibrinogen Angers showed a novel helical structure in place of hole 'a' on the outer edge of γD likely to have a negative impact on fibrinogen assembly and secretion.
CONCLUSION
The mechanism by which FSD mutations generate hepatic intracellular inclusions is still not clearly established although the promotion of aberrant intermolecular strand insertions is emerging as a likely cause. Reporting new cases is essential in the light of novel opportunities of treatment offered by increasing knowledge of the degradation pathway and autophagy.
Fibrinogen storage disease (FSD) is characterized by hypofibrinogenemia and hepatic inclusions due to impaired release of mutant fibrinogen which accumulates and aggregates in the hepatocellular endoplasmic reticulum. Liver disease is variable.
AIM
We studied a new Swiss family with fibrinogen Aguadilla. In order to understand the molecular peculiarity of FSD mutations, fibrinogen Aguadilla and the three other causative mutations, all located in the γD domain, were modelled.
METHOD
The proband is a Swiss girl aged 4 investigated because of fatigue and elevated liver enzymes. Protein structure models were prepared using the Swiss-PdbViewer and POV-Ray software.
RESULTS
The proband was found to be heterozygous for fibrinogen Aguadilla: FGG Arg375Trp. Familial screening revealed that her mother and maternal grandmother were also affected and, in addition, respectively heterozygous and homozygous for the hereditary haemochromatosis mutation HFE C282Y. Models of backbone and side-chain interactions for fibrinogen Aguadilla in a 10-angstrom region revealed the loss of five H-bonds and the gain of one H-bond between structurally important amino acids. The structure predicted for fibrinogen Angers showed a novel helical structure in place of hole 'a' on the outer edge of γD likely to have a negative impact on fibrinogen assembly and secretion.
CONCLUSION
The mechanism by which FSD mutations generate hepatic intracellular inclusions is still not clearly established although the promotion of aberrant intermolecular strand insertions is emerging as a likely cause. Reporting new cases is essential in the light of novel opportunities of treatment offered by increasing knowledge of the degradation pathway and autophagy.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1111/hae.12719
- PMID 25990487
- Persistent URL
- https://sonar.ch/global/documents/6420
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